Inhibitors of prolyl oligopeptidase (PREP) as novel candidates for tackling synucleinopathies: insight in structural, thermodynamic and kinetic parameters that determine inhibitor potential to block PREP-promoted alpha-Synuclein aggregation

Inadequate perfusion, oxygen limitation and cell metabolic changes, are key factors contributing to the formation of an acidic microenvironment in tumors.1 Two pivotal adaptations of tumor cells, related to maintaining intracellular pH and homeostasis in an acidic environment, have recently received significant attention: (1) the presence of chronic autophagy and (2) the overexpression of carbonic anhydrases (CAs), mainly CA IX and CA XII. Aiming to counter these essential tumor survival processes, the proposal deals with discovering and thoroughly evaluating novel autophagy inhibitors and and dual [autophagy-CA] inhibitors. The following three Work Packages will be elaborated during the course of the project: 1) Biopharmaceutical optimization of the host's Atg4B-inhibitor set. 2) Design and synthesis of dual [Atg4B-CA] inhibitors. 3) Biological characterization of Atg4B- and hybrid [Atg4B-CA] inhibitors in acidic cancer cell cultures and in an animal model of colorectal cancer.

Keywords:MOUSE MODELS, PHARMACOLOGY, MEDICINAL CHEMISTRY

Disciplines:Inorganic chemistry, Organic chemistry, Theoretical and computational chemistry, Other chemical sciences, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences

Project type:Collaboration project